Gestational diabetes mellitus (GDM) has short and long-term consequences for both the mother and her offspring. Women with GDM are more likely to deliver a large for gestational (LGA) infant and up to 50% of them will develop type 2 diabetes. However, up to half of women with GDM have no known risk factors, suggesting that other factors must be involved. Biomarkers associated with various metabolic pathways (insulin resistance, inflammation and oxidative stress) might be useful for identifying women at risk of GDM who could be targeted for prevention and may also further our understanding of the pathophysiology of GDM and its consequences. The metabolic and hormonal changes intrinsic to pregnancy make it important to assess these metabolic biomarkers before pregnancy to determine the temporal sequence of the associations. In three primary aims we propose to evaluate whether biomarkers of: 1) insulin resistance (adiponectin, HMW adiponectin, Fetuin-A and LDL-C particle size), 2) inflammation (CRP), and 3) oxidative stress (GGT) assessed before pregnancy, are associated with increased risk GDM. We will explore in the secondary aims whether: 4) pregravid levels of adiponectin and its isoforms are associated with the risk of having a LGA infant and whether this association is mediated by GDM; 5) among the women with GDM, pre-gravid levels of biomarkers of insulin resistance, inflammation, and oxidative stress and their long-term changes are associated with T2DM and degree of insulin resistance. We propose a nested case-control study within a multi-ethnic cohort of 4,084 women who took part in the Kaiser Permanente Northern California (KPNC) multiphasic health checkup (MHC) exam between 1984-1996, had serum samples stored, and had a subsequent pregnancy. We will study 235 women with GDM and 470 normoglycemic control women matched on year of MHC exam, age at MHC exam and age at pregnancy. No studies to date have examined biomarkers of metabolic risk before pregnancy and risk of GDM. This study will fill a gap in scientific knowledge by determining if pregravid biomarkers, measured among healthy young women, are associated with the risk of GDM, a metabolic alteration occurring early in life. This research could have translational value in the prevention of GDM its progression to T2DM, and health sequelae in their offspring. PUBLIC HEALTH RELEVANCE: The incidence of GDM is increasing in the United States, however much remains unknown about its underlying cause. This study will determine for the first time if the proposed pregravid biomarkers measured among healthy young women are associated with the risk of GDM, excessive fetal growth (LGA) and progression to type 2 diabetes. Identification of pregravid metabolic biomarkers of GDM and its adverse health consequences may give insights to the underlying causes leading to the development of GDM and its consequences. This information can be used to inform strategies for GDM and diabetes prevention.